Angiotensin II–Independent Angiotensin-(1–7) Formation in Rat Hippocampus: Involvement of Thimet Oligopeptidase

The involvement and relevance of the renin–angiotensin system have been established clearly in cardiovascular diseases, and renin–angiotensin system involvement has also been investigated extensively in the central nervous system. Angiotensin II acts classically by binding to the AT1 and AT2 recepto...

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Published in:	Hypertension (Dallas, Tex. 1979) Vol. 62; no. 5; pp. 879 - 885
Main Authors:	Pereira, Marilia G.A.G, Souza, Laura L, Becari, Christiane, Duarte, Diego A, Camacho, Fabio R.B, Oliveira, José Antônio C, Gomes, Marcelo D, Oliveira, Eduardo B, Salgado, Maria Cristina O, Garcia-Cairasco, Norberto, Costa-Neto, Claudio M
Format:	Journal Article
Language:	English
Published:	Hagerstown, MD American Heart Association, Inc 01-11-2013 Lippincott Williams & Wilkins
Subjects:	Angiotensin I - biosynthesis Animals Arterial hypertension. Arterial hypotension Biological and medical sciences Blood and lymphatic vessels Cardiology. Vascular system Epilepsy - metabolism Female Hippocampus - metabolism Medical sciences Metalloendopeptidases - metabolism Peptide Fragments - biosynthesis Proto-Oncogene Proteins - metabolism Rats Rats, Wistar Receptors, G-Protein-Coupled - metabolism Renin-Angiotensin System - physiology Rat Peptide hormone Central nervous system Metalloendopeptidases Cardiovascular disease Encephalon Octapeptide renin―angiotensin system Tumor Angiotensin II Biological receptor Hypertension Enzyme Rodentia Thimet oligopeptidase Mass Peptidases Vertebrata Renin angiotensin system Mammalia Animal angiotensin-(1―7) Hydrolases Circulatory system Formation angiotensin-(1―7) receptor Mas angiotensins Hippocampus angiotensin-(1–7) renin–angiotensin system angiotensin-(1–7) receptor Mas central nervous system thimet oligopeptidase
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Summary:	The involvement and relevance of the renin–angiotensin system have been established clearly in cardiovascular diseases, and renin–angiotensin system involvement has also been investigated extensively in the central nervous system. Angiotensin II acts classically by binding to the AT1 and AT2 receptors. However, other pathways within the renin–angiotensin system have been described more recently, such as one in which angiotensin-(1–7) (Ang-(1–7)) binds to the receptor Mas. In the central nervous system specifically, it has been reported that this heptapeptide is involved in learning and memory processes that occur in central limbic regions, such as the hippocampus. Therefore, this prompted us to investigate the possible role of the Ang-(1–7)–receptor Mas pathway in epileptic seizures, which are also known to recruit limbic areas. In the present study, we show that Ang-(1–7) is the main metabolite of angiotensin I in rat hippocampi, and, strikingly, that thimet oligopeptidase is the main enzyme involved in the generation of Ang-(1–7). Furthermore, elevations in the levels of thimet oligopeptidase, Ang-(1–7), and of receptor Mas transcripts are observed in chronically stimulated epileptic rats, which suggest that the thimet oligopeptidase–Ang-(1–7)–receptor Mas axis may have a functional relevance in the pathophysiology of these animals. In summary, our data, which describe a new preferential biochemical pathway for the generation of Ang-(1–7) in the central nervous system and an increase in the levels of various elements of the related thimet oligopeptidase–Ang-(1–7)–receptor Mas pathway, unveil potential new roles of the renin–angiotensin system in central nervous system pathophysiology.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0194-911X 1524-4563
DOI:	10.1161/HYPERTENSIONAHA.113.01613